Despite a large volume of basic scientific work over the past year, no effective treatment has yet been developed for patients with symptomatic sickle cell hemoglobinopathy. The main objective of this project is the development of an effective and safe extracorporeal therapy for sickle cell disease. The imidoester methyl acetimidate (MAI) shows many favorable properties. It prevents sickling in vitro at relatively low concentrations without significant detrimental effects upon the cellular integrity of the erythrocytes. Hemoglobin oxygen affinity, although increased, remains within the physiologic range. Despite the fact that MAI is a monofunctional imidoester, it establishes globin subunit crosslinkages within as well as between hemoglobin tetramers. Studies are in progress to identify the sites of hemoglobin amidination following MAI treatment, as well as to quantitate the reaction. The results will hopefully clarify the mechanism of the antisickling effect of MAI and lead to clinical studies in patients, first of erythrocyte survival times and ultimately to the development of extracorporeal therapy in animals and finally clinical trials in patients, assuming that criteria of safety are satisfactorily fulfilled.